The dopamine transporter (DAT) has been previously identified as a principal brain receptor site that has been correlated with the rewarding and euphoric properties of cocaine. It is required for the actions of each of the current dopamine-selective toxins that produce the best models of Parkinsons disease. Analyses of DAT structure- function relationships continued during this year with further characterization of the roles of nonpolar aromatic amino acids, especially phenylalanines and prolines, in transporter function. These studies have been extended to studies of TM domain mutant combinations, allowing identification, for the first time, of domain-domain interactions through kinetic analyses of information from altered affinities. These studies continue to identify selective DAT regions, and larger domains that are comprised of several interacting regions, that are important for cocaine analog recognition or for dopamine transport. These insights continue to help in design and identification of selective structure-function features of small molecule compounds possibly active in vivo as cocaine antagonists. These analyses revealed candidate compounds with some in vitro selectivity for cocaine analog recognition compared with dopamine uptake and reduced cross-reactivity with other sites. - Cocaine Parkinson's disease ADHD monoamine transporters structure/activity relationships site directed mutagenesis